Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid modification

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg evolocumab, alirocumab) are monoclonal antibodies that block PCSK9-mediated breakdown of low-density lipoprotein (LDL) receptors. This increases the number of LDL receptors available for cellular uptake of LDL cholesterol (LDL-C), resulting in reduced circulating concentrations of LDL-C by 50 to 60%Krychtiuk KA, 2020.

In a randomised controlled trial of patients with established atherosclerotic cardiovascular disease (ASCVD), the addition of a PCSK9 inhibitor to statin therapy produced a modest reduction in cardiovascular events over 2 years, but no reduction in mortalitySabatine, 2017 ¹. Do not add a PCSK9 inhibitor to statin therapy unless ezetimibe has been ineffective or not tolerated.

The effect of PCSK9 inhibitors on cardiovascular events in primary prevention of ASCVD has not been studied; however, genetic studies of people with PCSK9 loss-of-function mutations have shown they have reduced LDL-C concentrations and a reduced risk of coronary artery diseaseCohen, 2006 Ference, 2016 ² ³.

Consider adding a PCSK9 inhibitor if the LDL-C target is not achieved with the maximum tolerated dose of a statin and ezetimibe. Use:

1alirocumab 75 to 150 mg subcutaneously every 2 weeks, or 300 mg subcutaneously every 4 weeks⁴ alirocumab alirocumab alirocumab

1evolocumab 140 mg subcutaneously every 2 weeks, or 420 mg subcutaneously every 4 weeks⁵ ⁶. evolocumab evolocumab evolocumab

At the time of writing, PCSK9 inhibitors have not been associated with any notable adverse effects other than injection site reactions.

¹ Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376(18):1713-22. URL Return

² Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354(12):1264-72. URL Return

³ Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016;375(22):2144-53. URL Return

⁴ At the time of writing, alirocumab is subsidised on the PBS for nonfamilial hypercholesterolaemia under specific criteria (including patients unable to tolerate other lipid-lowering drugs, patients with LDL-C concentrations above 2.6 mmol/L despite statin and ezetimibe therapy, and only if started by a specialist). It is also subsidised for familial heterozygous hypercholesterolaemia meeting specific criteria. See the PBS website for current information.Return

⁵ At the time of writing, evolocumab is subsidised on the PBS for nonfamilial hypercholesterolaemia under specific criteria (including patients unable to tolerate other lipid-lowering drugs, and patients with LDL-C concentrations above 1.8 mmol/L despite statin and ezetimibe therapy). It is also subsidised for familial homozygous or heterozygous hypercholesterolaemia meeting specific criteria. See the PBS website for current information.Return

⁶ Patients with homozygous familial hypercholesterolaemia may require a higher dose of evolocumab (420 mg every 2 weeks). Return